HEPATOCYTE GROWTH-FACTOR SCATTER FACTOR AND HEPATOCYTES ARE POTENT DOWNREGULATORS OF TYROSINASE EXPRESSION IN B16 MELANOMA-CELLS

Reiterated selection in vivo of B16 murine melanoma cells for enhanced liver metastatic ability yielded a cell line(B16-LS9) dramatically ov erexpressing a constitutively active hepatocyte growth factor/scatter factor (HGF/SF) receptor, the product of the c-met proto-oncogene. Mos t likely because of their overexpressing c-met, B16-LS9 cells appear t o be more responsive than parental B16-F1 cells to HGF stimulation, in terms of motility, invasion, and growth. They are also more pigmented , and express higher levels of tyrosinase as compared to parental B16- F1 cells. Therefore, we set out to explore whether HGF/SF and the live r might influence the differentiation state of B16 cells. We found tha t HGF/SF and MSH, two factors which reportedly have a strong influence on the phenotype and the malignant behavior of melanoma cells, may ac t at different levels, and with opposite results, on the regulation of gene expression. in fact, while MSW induces, at the transcriptional l evel, an increase in the production of both c-met and tyrosinase, HGF/ SF, in contrast, promotes a decrease in the expression of both c-met a nd tyrosinase, however at a posttranscriptional level. These two oppos ite effects can counter-balance each other, when the cells are treated with both factors at the same time, apparently through a mechanism in volving MAP kinase activation. The effects were, however, additive whe n morphological changes were considered. Most intriguingly, we also de scribe a very strong downregulatory activity, limited to tyrosinase Ex pression, by hepatocytes in coculture with B16 cells. This activity al so at the posttranscriptional level, is much stronger than that exerte d by HGF/SF, and appears to be due to a labile soluble factor produced by the hepatocytes. J. Cell. Biochem. 71 :264-276, 1998. (C) 1998 Wil ey-Liss, Inc.